Molecular Bases of Disease
Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairmentRAGE mediates neurodegeneration in sepsis

https://doi.org/10.1074/jbc.M117.786756Get rights and content
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Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202–phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nɛ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

amyloid-β (Aβ)
neurodegeneration
neuroinflammation
receptor for advanced glycation end products (RAGE)
sepsis
Tau protein (Tau)

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This work was supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (to D. P. G., J. C. F. M., J. Q., and F. D.-P.), FundaçΔo de Amparo à Pesquisa do Estado do Rio Grande do Sul (to D. P. G. and J. C. F. M.), FundaçΔo de Amparo à Pesquisa e InovaçΔo do Estado de Santa Catarina (to J. Q. and F. D.-P.), Propesq/UFRGS (to D. P.G. and J. C. F. M.), FundaçΔo CAPES, Instituto Cérebro e Mente (to J. Q.) and UNESC (to T. B., J. Q., and F. D.-P.). The authors declare that they have no conflicts of interest with the contents of this article.